This study is the first to investigate the associations between serum IgM, IgG, IgA, and IgE levels and the risk of all-cause mortality in centenarians in Hainan Province, China. Further, this is the first study of serum immunoglobulins and risk of death in centenarians with large-scale, long-term follow-up. Our study not only found that a lower serum IgM concentration was associated with mortality risk in centenarians, but also observed that this trend was nonlinear, such that a higher serum IgM level was associated with a lower mortality risk in centenarians before reaching a plateau. After adjusting for population characteristics, comorbidities, and other immune indicators in multivariate Cox regression analyses, the change in serum IgM concentration still significantly correlated with the risk of death, to a greater degree than IgG, IgA, and IgE level, suggesting that serum IgM is more suitable for predicting the overall risk of death in centenarians, and that it may be useful as an independent predictor of death.

IgM, part of the body’s adaptive humoral immune response against foreign pathogens, is the first type of antibody secreted by the adaptive immune system in response to foreign antigens [17]. It can be divided into natural IgM and antigen-induced IgM, which can be membrane-bound or secreted [18]. Natural IgM plays multiple roles in homeostasis, including promoting the clearance of apoptotic or dead cells, B cell survival signaling, and autoimmune disease prevention [19, 20]. IgM is increasingly recognized for its diverse roles in immune homeostasis, particularly in the context of infectious and non-infectious diseases. It serves as a frontline defense against a spectrum of pathogens, including protozoan parasites such as malaria, fungal infections, and is implicated in the pathogenesis of allergic conditions like asthma, as well as viral infections such as influenza A [21]. At mucosal sites, both natural IgM and antigen-induced IgM help shape a healthy microbiota [22]. Notably, IgM is thought to play a pivotal role in enhancing mucosal tolerance and, in conjunction with IgA, influencing the structure and function of the microbiota [21]. IgM has been observed to foster the proliferation of bacterial species that are instrumental for maintaining a balanced gut homeostasis, such as Firmicutes, including Bacillus cereus, Lachnospiraceae species, and Ruthenibacterium species [23, 24]. These bacteria are known to contribute to various metabolic processes in the gut, which are essential for the host’s immune response and overall health. In addition, natural IgM is associated with the recognition and clearance of premalignant cells because natural IgM antibodies are able to recognize carbohydrate-patterned autoantigens and rapidly activate complement [25]. Natural IgM antibodies can also inhibit microvesicle-driven coagulation and thrombosis [26]. These characteristics suggest that IgM may contribute to the ability of centenarians to avoid various fatal diseases.

Previous studies on IgM have mostly focused on autoimmune diseases [27], cancer [28, 29], and infectious diseases [30]. However, IgM can also protect blood vessels by neutralizing atherosclerotic antigens, and the level of natural IgM negatively correlates with atherosclerosis progression, carotid artery thickness, and the frequency of cardiovascular events [31,32,33]. In a study of 1,753 volunteers, Ramzi Y. Khamis and his colleagues discovered that, in patients with hypertension, the higher total serum IgM levels are independent predictors of freedom from cardiovascular events in general and from coronary heart disease in particular [34]. Our findings echo those of the Ramzi Y. Khamis study, suggesting that there is a negative correlation between serum IgM level and all-cause mortality in centenarians. The higher the serum IgM level, the lower the mortality risk, up to the point that the risk plateaus. Phillips AC et al. investigated a cohort of 4255 Vietnam-era, former US army personnel (the Vietnam Experience Study) who served during the Vietnam War and found that elevated levels of immunoglobulin were associated with an increased risk of all-cause mortality and deaths attributed to “other” causes, predominantly infectious diseases [15]. This finding contrasts with our results, which may be attributed to several factors. Firstly, the study cohort comprised exclusively male military personnel, whereas in our study, females constituted 81.2% of the population, potentially contributing to the observed discrepancies. Secondly, the age at baseline in the Phillips AC et al. study was 38.6 ± 2.68 years for decedents and 38.3 ± 2.51 years for survivors. Thirdly, the study did not exclude participants with infectious diseases, whereas our study rigorously excluded such individuals. Additionally, centenarians may possess unique immune regulatory mechanisms that contribute to their health and longevity. Florinda et al. studied the serum immunoglobulin levels of 166 subjects (20–106 years old) and found that IgG and IgA levels increased in an age-related manner, whereas IgE levels remained unchanged and serum IgD and IgM levels decreased with age; the age-related decline in IgM was only statistically significant in women, which may be related to the relatively small number of men in their sample (male: female = 49:117) [35]. However, in 2010, Colonna-Romano and colleagues conducted a comparative experiment of immunosenescence in the offspring of 29 centenarians and 25 age-matched controls. The experiment found that naïve B cells and the IgM ratio were higher in the offspring of centenarians compared with the control group [5]. Similarly, our study found that IgM level was associated with the mortality risk of centenarians in an “L” pattern. With a higher serum IgM level, the mortality risk of centenarians decreased before leveling off. At the same time, we found that 93.3% of centenarians’ serum IgM levels were at the normal level, which confirmed that IgM was associated with long life, likely owing to its ability to help centenarians resist disease, so IgM could be useful as an independent predictor of all-cause mortality in centenarians. To date, the relationship between IgM and all-cause mortality in centenarians has not been fully explored. Therefore, this study provides the first evidence for the relationship between serum IgM levels and all-cause mortality in centenarians.

IgG is the most abundant type of immunoglobulin in the human body, and IgG antibodies usually have high affinity, making them particularly effective at neutralizing secreted bacterial toxins and viral docking molecules used to enter cells [36]. IgA is secreted at mucosal surfaces (such as the mouth, nose, and gastrointestinal tract), where they are the first line of defense against surface infections and pathogen colonization [37]. Compared with other isotypes, IgE is present at very low concentrations in the body; it is related to responses to parasitic infections, such as those caused by helminths [38]. Interestingly, in our study, the percentages of centenarians with higher IgA, IgG, and IgE above the normal ranges were approximately 30%, 50%, and 70%, respectively, and there were no centenarians with IgG, IgA, and IgE below the normal range, which suggested that the immune function of the centenarians was normal or enhanced. This is similar to the findings of an earlier observational report, that the immune function of healthy centenarians is closer to that of young people than that of 70-year-old individuals [39]. In another study, the biological age of supercentenarians (> 110 years old) was estimated by an epigenetic clock, and their epigenetic age was found to be 8.6 years younger than their actual age [40]. Franceschi et al., based on their study of “healthy” centenarians (i.e., subjects in good mental and physical condition), found evidence of sustained remodeling of the immune system, rather than general deterioration [2, 41]. The function of the immune system can regulate the speed of aging to slow down the inevitable aging process, which plays a key role in most chronic diseases of the elderly. The literature on immunosenescence has mainly focused on T cells [42, 43], while the B cell compartment is also affected in older adults. Colonna et al. found that changes in B cell subsets in centenarian offspring may mark successful or unsuccessful aging, suggesting B cell count could be used as a biomarker of human lifespan, allowing evaluation of anti-aging treatment [5]. Proteomic analysis revealed that healthy centenarians exhibited greater B cell-mediated immune responses, including antibody production, compared with controls from the same geographical area who died prematurely [44]. Our results also support the relationship between immunoglobulins secreted by B lymphocytes and longevity, adding strong evidence for the study of healthy immune system aging, especially the relationship between healthy aging and immunoglobulins.

This study focused on the long-lived population in Hainan, China, which is one of the few long-lived island populations in the world, with a large sample of centenarians. On the one hand, the study of long-lived people is conducive to the discovery of indicators closely related to health and longevity. On the other hand, serum IgM is more suitable for predicting the overall mortality risk of centenarians, with the potential for use as an independent predictor of death. Circulating immune proteins are easy to obtain and widely used, and can be used as immune biomarkers to monitor the susceptibility of older individuals to aging-related diseases.

This study has the following advantages. It uses the scarce resource of centenarians as a model of successful aging, with a follow-up of approximately 30 months. This may be the first study on the relationship between serum IgM, IgG, IgA, and IgE levels and mortality risk in a large, prospective cohort of centenarians. Our study shows that serum IgM level can be used as an independent risk factor to predict the mortality risk of centenarians, and further exploration may reveal it to be a potential biomarker of a long, healthy lifespan. The study also has some shortcomings. First, the study population is mainly derived from the Chinese Han population and the oldest adult population, so our results may not be applicable to populations with a more diverse ethnic composition or younger individuals. Second, the association between the combined levels of IgM, IgG, IgA, and IgE and the risk of death was not analyzed; this will be further explored in the next study. Third, we only explored the relationship between levels of IgM, IgG, IgA, and IgE and the risk of all-cause death. Further research will be required to determine the association of immunoglobulin levels with specific causes of death. Fourthly, we did not detect circulating B cell subsets and immunoglobulin subclasses in the population, however, we plan to detect and analyze them in future studies.